Iridium Complexes for Intracellular Transfer Hydrogenation and Their Potential Biological Applications



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Transfer hydrogenation is a transformation that has been studied for over 100 years and used widely in chemical synthesis. Although transfer hydrogenation can be performed by natural enzymes such as dehydrogenases, small-molecule intracellular metal catalysts (SIMCats) that are capable of catalyzing such reactions inside living systems have recently been discovered by our research group and others. We found that pentamethylcyclopentadienyl iridium(III) (CpIr) complexes bearing 2-pyridinecarboxamidate ligands are capable of mediating catalytic hydride transfer from either NADH or formate to aldehydes in PBS buffer and cell culture media. These iridium catalysts are tolerant of moderate concentrations of biological nucleophiles, including thiols such as glutathione and cysteine. To design more efficient catalysts for intracellular transfer hydrogenation, we performed structure-activity relationship (SAR) studies of a series of CpIr pyridinecarboxamidate complexes. Chemical functionalization of the pyridine ring was found to have larger effects on the catalytic activity of the iridium complexes than functionalization of the N-amide substituent. Our NMR and UV-vis spectroscopic experiments showed that adding electron donating groups to the pyridine ring increased the hydride donor ability of the corresponding Ir-H complexes, which could enhance the rates of hydride transfer from Ir-H species to benzaldehyde by up to 28x, and lower the activation energy associated with the transfer hydrogenation process by up to 3 kcal/mol. More electron-rich Ir complexes were also found to have greater chemical stability under physiological conditions. We have also discovered that our Cp*Ir complexes can efficiently reduce cytotoxic α,β-unsaturated aldehydes to non-toxic alcohols in cell culture media. Inductively coupled plasma-mass spectrometry (ICP-MS) analysis demonstrated that these iridium complexes could be retained inside NIH 3T3 and SH-SY5Y cells, as well as zebrafish. In our aldehyde detoxification experiments, cells that were pre-treated with our iridium complexes showed up to 30% greater survival compared to those that were pre-treated with conventional aldehyde scavengers such as carnosine or phloretin. The Ir complexes could also increase the viability of zebrafish in acrolein contaminated water by up to 40%. Our work could lead to the creation of new therapeutic methods in treating diseases associated with cytotoxic aldehydes such as metabolic disorders, neurodegenerative disorders, or cancers.



Iridium, Transfer hydrogenation, Catalysis, Aldehyde detoxification


Portions of this document appear in: Ngo, Anh H., Sohini Bose, and Loi H. Do. "Intracellular chemistry: integrating molecular inorganic catalysts with living systems." Chemistry–A European Journal 24, no. 42 (2018): 10584-10594. And in: Polukeev, Alexey V., Pavel V. Petrovskii, Alexander S. Peregudov, Mariam G. Ezernitskaya, and Avthandil A. Koridze. "Dehydrogenation of alcohols by bis (phosphinite) benzene based and bis (phosphine) ruthenocene based iridium pincer complexes." Organometallics 32, no. 4 (2013): 1000-1015. And in: Ngo, Anh H., Miguel Ibañez, and Loi H. Do. "Catalytic hydrogenation of cytotoxic aldehydes using nicotinamide adenine dinucleotide (NADH) in cell growth media." ACS Catalysis 6, no. 4 (2016): 2637-2641.